Combination rivaroxaban, aspirin reduces major adverse limb events in PAD

Issue: May 2018

ORLANDO, Fla. — Patients with lower-extremity peripheral artery disease have a significantly worse prognosis after experiencing a major adverse limb event, but combination therapy with rivaroxaban and aspirin may be effective for prevention.

Perspective from Natalie S. Evans, MD, MS

Sonia S. Anand, MD, PhD, from the Population Health Research Institute at McMaster University, presented findings from a subanalysis of the randomized, double blind, placebo-controlled COMPASS trial, which randomly assigned more than 27,000 patients with CAD or PAD to treatment with a combination of aspirin and low-dose rivaroxaban (Xarelto, Janssen), rivaroxaban alone or aspirin alone. Of these patients, 6,391 had lower-extremity PAD and 128 experienced a major adverse limb event, defined as severe limb ischemia requiring intervention or major amputation of vascular cause.

Compared with aspirin alone, rivaroxaban plus aspirin significantly reduced major adverse limb events by 43% (HR = 0.57; 95% CI, 0.37-0.88) and total vascular amputations by 58% (HR = 0.42; 95% CI, 0.21-0.85). Combination therapy also was associated with a significant 24% reduction in all peripheral vascular outcomes — including acute limb ischemia, chronic limb ischemia, vascular interventions and vascular hospitalizations (HR = 0.76; 95% CI, 0.61-0.96), according to data presented at the American College of Cardiology Scientific Session.

Analysis of incidence rates per 100 person-years also showed significantly higher rates of death, amputation, and combined MACE and amputation among patients assigned aspirin alone.

In an evaluation of outcomes after a major adverse limb event in the trial, the cumulative incidence 1-year risk was 95.4% for subsequent hospitalization, 22.9% for vascular amputations, 8.7% for death and 3.8% for MACE, defined as a composite of CV death, MI or stroke.

Furthermore, the major adverse limb event was associated with a seven-fold increase in risk for hospitalizations (HR = 7.21; P < .0001), a nearly 200-fold increase in risk for total vascular amputations (HR = 197.5; P < .0001), a three-fold increase in risk for death (HR = 3.23; P < .0001) and a seven-fold increase in risk for MACE or total vascular amputations (HR = 7.56; P < .0001).

Anand noted that treatment after patients experienced a major adverse limb event varied considerably.

“Therapies after major adverse limb events are interesting and reflect the heterogeneity in treatments given to patients who suffer major adverse limb events,” she said during a presentation of the data.

After the index major adverse limb event, according to Anand, 63% of patients were maintained on the blinded randomized study drug, with physicians not knowing if the patients were receiving aspirin alone, rivaroxaban alone or combination aspirin and rivaroxaban. Among patients for whom unblinding occurred, 13% were put on single antiplatelet therapy, 10% on dual antiplatelet therapy, 2% on oral anticoagulants and 12% were left with no therapy.

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Patients who experienced major adverse limb events, as compared with those who did not, more often had a prior history of peripheral surgery or angioplasty (P < .0001) and prior limb amputation (P = .0001). They were also more likely to be Fontaine class 3 or 4 at baseline (P < .0001) and were more likely to be randomly assigned to the aspirin alone treatment arm (P = .01).

“Major adverse limb events are associated with a poor prognosis,” Anand said. “Compared to aspirin, the rivaroxaban/aspirin combination prevents major adverse limb events, vascular interventions and total peripheral vascular outcomes.” – by Melissa Foster

References:

Anand SS. Featured Interventional Clinical Research III. Presented at: American College of Cardiology Scientific Session; March 10-12, 2018; Orlando, Fla.

Anand SS, et al. J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2018.03.008.

Disclosure: Anand reports she has received honoraria and consultant fees from Bayer and Novartis.

Perspective

Natalie S. Evans, MD, MS

We have known for a long time in the PAD community that patients with critical limb ischemia and acute limb ischemia have terrible outcomes, so these data are encouraging.

The patients who were on low-dose rivaroxaban plus aspirin had no difference in major CV events or amputations after adverse limb events, while those on aspirin had a tenfold increase in amputations after major adverse limb events. This is important because we know from earlier data that these patients have high rates of morbidity and mortality, and to be able to reduce those amputations is wonderful.

I believe that when we finally get the dosing, many people will incorporate this drug into their treatment regimens, which is a major development because we haven’t had a new drug for PAD in my entire career. This potentially opens up new horizons in terms of saving limbs and saving lives, which is extremely important.

Moving forward, once we have the drug in the United States, I suspect there will be an update of the guidelines. After that, I think there will probably be a lot of early adopters in the vascular medicine community, although the adoption may not be as widespread outside in other specialties.

Natalie S. Evans, MD, MS

Staff Physician, Section of Vascular Medicine

Cleveland Clinic

Disclosures: Evans reports no relevant financial disclosures.